Discovery of a small molecule targeting IRA2 deletion in budding yeast and neurofibromin loss in malignant peripheral nerve sheath tumor cells

• Published in: Molecular cancer therapeutics 2011-09, Vol.10 (9), p.1740-1750
• Main Authors: Wood, Matthew, Rawe, Melissa, Johansson, Gunnar, Pang, Shu, Soderquist, Ryan S, Patel, Ami V, Nelson, Sandra, Seibel, William, Ratner, Nancy, Sanchez, Yolanda
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cell Line; Drug Discovery; Epistasis, Genetic; Gene Deletion; Gene Expression Regulation, Fungal; Gene Expression Regulation, Neoplastic; GTPase-Activating Proteins - genetics; High-Throughput Screening Assays; Humans; Nerve Sheath Neoplasms - drug therapy; Neurofibromin 1 - genetics; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Protein Kinases - genetics; Pyrazoles - chemistry; Pyrazoles - pharmacology; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Sensitivity and Specificity; Small Molecule Libraries; Thiourea - analogs & derivatives; Thiourea - chemistry; Thiourea - pharmacology; Transcription, Genetic
• ISSN: 1535-7163; 1538-8514; 1538-8514
• DOI: 10.1158/1535-7163.MCT-11-0309

Malignant peripheral nerve sheath tumor (MPNST) is a life-threatening complication of neurofibromatosis type 1 (NF1). NF1 is caused by mutation in the gene encoding neurofibromin, a negative regulator of Ras signaling. There are no effective pharmacologic therapies for MPNST. To identify new therapeutic approaches targeting this dangerous malignancy, we developed assays in NF1(+/+) and NF1(-/-) MPNST cell lines and in budding yeast lacking the NF1 homologue IRA2 (ira2Δ). Here, we describe UC1, a small molecule that targets NF1(-/-) cell lines and ira2Δ budding yeast. By using yeast genetics, we identified NAB3 as a high-copy suppressor of UC1 sensitivity. NAB3 encodes an RNA binding protein that associates with the C-terminal domain of RNA Pol II and plays a role in the termination of nonpolyadenylated RNA transcripts. Strains with deletion of IRA2 are sensitive to genetic inactivation of NAB3, suggesting an interaction between Ras signaling and Nab3-dependent transcript termination. This work identifies a lead compound and a possible target pathway for NF1-associated MPNST, and shows a novel model system approach to identify and validate target pathways for cancer cells in which NF1 loss drives tumor formation.